Validation apparatus for validating a force testing machine, method of validating a force testing machine and method of measuring forces

ABSTRACT

A force testing machine (FTM) validation apparatus is disclosed for validating a test process involving a force testing machine to measure forces involved in operation of a syringe arrangement. Particularly a syringe arrangement that includes a staked-in needle prefilled syringe and a needle safety device cooperating with the staked-in needle prefilled syringe. The FTM validation apparatus includes a syringe arrangement surrogate, and a holder arranged to support the syringe arrangement surrogate in a predefined position and orientation in the force testing machine. The syringe arrangement surrogate includes a break loose part arranged to mimic a break loose force of the syringe arrangement and an injection force part arranged to mimic an injection force of the syringe arrangement. Methods are also disclosed for validating a test process that measures forces involved in operation of a syringe arrangement and for measuring forces involved in operation of the syringe arrangement.

CROSS-REFERENCE TO RELATED APPLICATION

The present application is a continuation of prior U.S. application Ser.No. 16/769,403, filed Jun. 3, 2020, now U.S. Pat. No. 11,460,361, whichis a national stage application of PCT/EP2018/083923, filed Dec. 7,2018, which claims the benefit of EP 17206008.9, filed Dec. 7, 2017,each of which is incorporated by reference herein in its entirety.

TECHNICAL FIELD

The present invention relates to a validation apparatus for validating atest process involving a force testing machine (FTM) to measure forcesinvolved in operation of a syringe arrangement. Syringe arrangements maycomprise a prefilled syringe provided with a staked-in needle and aneedle safety device. The present invention also relates to a method ofvalidating a test process involving a FTM to measure forces involved inoperation of a syringe arrangement, by employing such a FTM validationapparatus, as well as to a method of measuring forces involved inoperation of a syringe arrangement, wherein the measuring process hasbeen validated by the aforementioned validating method.

Such validation apparatus and methods can be used for ensuring that thetest equipment and test process deployed in connection with thedevelopment and the manufacturing of a syringe arrangement is reliableand yields consistent results which accurately and precisely reflect theoperational reality of the syringe arrangement being tested.

BACKGROUND

In general, pharmaceutical, biotechnological and medical products arestrictly regulated to ensure that they are fit for the intended use andthat they do not have inappropriate side effects. Not only the products,but also related processes need to comply with quality assuranceprograms to prevent mistakes or defects in manufactured products andavoiding issues when delivering solutions or services to customers. Inparticular, in the context of pharmaceutical or medical industries, ittypically is of paramount importance that products, devices andprocesses consistently and reliably produce expected results. Forensuring this, usually processes and/or products or devices arevalidated.

The term “validation” as used herein relates to confirming by objectiveevidence that requirements or conditions of a specific application or aspecific use are met. It typically involves production of documentedevidence that a process carried out, e.g. in testing, maintains at allstages the desired level of compliance with pre-establishedspecifications. The outcome of a stable, validated process should thenbe, invariably, the production of a product which is, in real life,capable to perform the task as intended and declared. Validation is arequirement of food, drug and pharmaceutical regulating agencies such asthe United States Food and Drug Administration (FDA). Good manufacturingpractices guidelines issued by such agencies stipulate that a set ofindependent procedures be carried out to check if a final product willmeet predetermined specifications and requirements of its intendedpurposes and will consistently perform within a given range. Validationis therefore essential to receive product approval by regulatingagencies.

Validation may also encompass the qualification of systems and equipmentemployed for developing, testing and manufacturing a finalpharmaceutical product. In precision instruments, laboratory equipmentor specialized machinery, even minor inaccuracies can cause problems andlead to incomplete, contradictory or erroneous results. In particular,an incorrect system of validating a test equipment can lead to falseassumptions, eventually resulting in the impossibility to adhere toindustry norms and obtain a product fit for the intended use.

Typically, quality assurance is also required for the operation ofsyringe arrangements such as ready-to-use prefilled syringes. Thereby,forces involved when using such syringe arrangements during injectionare important for their secure and accurate operation. For example, whena force to be applied by a user to advance a plunger of the syringearrangement is too high such operation may be difficult or inaccurateand appropriate delivery quality cannot be assured. Therefore, suchinjection forces are measured wherein test processes involving a FTM andauxiliary equipment are often used.

However, it has been shown that known test processes often are not fullyreliable and their accuracy is affected by the inhomogeneity inbehaviour of the syringe arrangements used for testing. Furthermore,such test processes typically also have to be validated. However, sinceconventional testing on a multiplicity of actual product units, i.e. ofsingle syringe arrangements, is by definition destructive and a newproduct unit is needed at every repeated test, such validation of thetest process might be resource consuming and costly.

Therefore, there is a need for a validation apparatus allowing torepeatedly provide reliable and robust test data which realisticallyreflect the measuring of forces involved in testing operation of asyringe arrangement. There is also a concurrent need for validating moreaccurate test processes involving FTM in connection with the operationof a syringe arrangement.

DISCLOSURE OF THE INVENTION

According to the invention this need is settled by a force testingmachine (FTM) validation apparatus, by a method of validating a testprocess involving a force testing machine, and by a use as describedherein.

In one aspect, the present invention relates to a force testing machine(FTM) validation apparatus for validating a test process involving aforce testing machine. In the particular context of the invention theterm “validation” can be more specifically be understood as aconfirmation that the FTM validation apparatus and the associated testprocess reproducibly simulate the characteristics in the form offunctions of the syringe arrangement in application. The FTM is inparticular to be used to measure forces involved in operation of asyringe arrangement. The FTM validation apparatus is especiallyconceived to be used for validating a test process involving a FTM formeasuring forces during the operation of syringe arrangements,particularly comprising staked-in needle (SIN) prefilled syringes (PFS)and needle safety devices cooperating with the SIN PFS.

The FTM validation apparatus according to the present inventioncomprises a syringe arrangement surrogate and a holder arranged tosupport the syringe arrangement surrogate in a predefined position andorientation in the FTM. The holder is advantageously also used in thevalidated testing process for accurately positioning the syringearrangement to be tested. Thus, the holder typically does form part ofthe validated process or system.

The syringe arrangement surrogate is configured to simulate, or mimic, astandardized or other embodiment of a syringe arrangement. The syringearrangement can, for instance, comprise a syringe such as a staked-inneedle prefilled syringe (SIN PFS) dimensioned to administer 1.0milliliter or 2.25 milliliters of a pharmaceutical substance.

In the FTM validation apparatus, the syringe arrangement surrogatecomprises a break loose part, arranged to mimic a break loose force ofthe syringe arrangement, and an injection force part, arranged to mimican injection force of the syringe arrangement.

In the context of the present invention, the term “prefilled syringe”,abbreviated by the acronym PFS, relates to a syringe, whose barrel isfilled with a given dosage of pharmaceutical or drug substance. Suchprefilled syringe may be provided with a staked-in needle (SIN) or anadaptor to be connected with a suitable needle before application.

The term “drug” as used herein relates to a therapeutically activeagent, also commonly called active pharmaceutical ingredient (API), aswell as to a combination of plural such therapeutically activesubstances. The term also encompasses diagnostic or imaging agents, likefor example contrast agents (e.g. MRI contrast agents), tracers (e.g.PET tracers) and hormones, that need to be administered in liquid formto the patient.

The term “drug substance” or “pharmaceutical substance” as used hereinrelates to a drug as defined above formulated or reconstituted in a formthat is suitable for administration to the patient. For example, besidesthe drug, a drug substance may additionally comprise an excipient and/orother auxiliary ingredients. A particularly preferred drug substance inthe context of the invention can be a drug solution, in particular asolution for, e.g. subcutaneous, intramuscular, intradermal orintravitreal, injection via the syringe arrangement.

The term “drug product” as used herein relates to a finished end productcomprising a drug substance or a plurality of drug substances. Inparticular, a drug product may be a ready to use product having the drugsubstance in an appropriate dosage and/or in an appropriate form foradministration. For example, a drug product may include anadministration device such as a syringe arrangement or a prefilledsyringe or the like.

A syringe arrangement or syringe can be thought in more generic terms asa medicament delivery system, which can in principle be both manuallyoperated—as in a conventional syringe—or automatically operated, foradministering an appropriate dosage of prefilled pharmaceuticalsubstance in the body of human or animal patients. In the presentcontext, a syringe or syringe arrangement can also take the form ofautomatic injection devices, housing a container preventively filledwith a pharmaceutical substance, which, when operated, causes thecontainer to move in a proximal direction towards a delivery site of thepatient and a needle on the container to project out of the devicehousing to inject the therapeutic agent into a patient's body. Thisautomatism is typically achieved by a mechanism, which, when triggeredby an operator, automatically executes the delivery of the drug to thepatient. Therefore, the term “syringe” may also encompass injectiondevices intended for self-administration by patients, or foradministration by less experienced personnel, such as auto-injectiondevices. These devices are expressly designed to overcome manipulationand safety difficulties associated with administration of a drug througha needle-based delivery device by unskilled operators.

In preferred embodiments, the syringe arrangement comprises or is astaked-in needle prefilled syringes (SIN PFS). Such SIN PFS have shownto be comparably convenient to handle and use. In such syringes thepharmaceutical substance is provided in the interior of the syringe in asolved or other liquid form ready for being applied. Like this, the userreceives a ready-to-inject syringe, without the requirement to fill thepharmaceutical solution into the syringe or to manually assemble theneedle to the syringe body. The occurrence of injuries or inappropriatehandling during application can thereby be minimized.

Usually, SIN PFS comprise of a syringe body, a staked-in needle and arigid needle shield (RNS). The RNS can be the closure of the needlewhich aims for preventing accidental stick injuries, leaking ofpharmaceutical substance and entry of contaminations. Commonly, RNS havean inner elastomeric part which is adjacent to and incorporates theneedle and an outer solid part which can be made of a thermoset plasticmaterial or the like.

Moreover, when generally operating syringes, the break loose force isthe force required to overcome the static friction of a stopper of aplunger of a syringe in a syringe arrangement and to start moving theplunger from its storage extended position. First, it is necessary toovercome the resistance between a barrel of the syringe and a stopper ofthe plunger sliding along the barrel, to move the plunger head. By wayof example, if the break loose force increases too much, the spring inan auto-injector incorporated in the syringe arrangement may not be ableto overcome resistance induced by it, so that the injection cannotstart.

Further, in operation of syringes, injection force is the force requiredto maintain or sustain the movement of the plunger of a syringe orsyringe arrangement, once the static friction has been overcome, inorder to expel the content of the syringe. As the plunger stopper movesdown the syringe barrel, it encounters friction resistance until thesyringe barrel is emptied. This resistance can be part of the injectionforce or gliding force. Increased injection force can slow the motion ofthe plunger to the point that the injection time is unacceptably longand, in the worst-case scenario, it can stall the plunger and preventthe complete dosage from being delivered. More specifically, theinjection force may be the result of plural force components: theabovementioned friction between the plunger stopper and the internalwalls of a syringe body, or barrel; the fluid dynamic resistance, ordrag, exerted by the pharmaceutical substance, located inside thesyringe body and to be administered, on account of its viscosity; theresistance to be overcome for transferring the substance through aneedle of comparably small diameter; etc. It can also comprise acomponent of an initially different force to be applied due to an air tobe compressed before delivery of the drug substance. Thus, the injectionforce typically depends on a plurality of parameters such as viscosityof the substance, inner diameter of the needle, barrel, presence andsize of an air bubble etc. The injection force can be lower, the sameor, in some cases, also higher than the break loose force.

The holder of the FTM validation apparatus can be integral with thesyringe arrangement surrogate, e.g. it can be composed of particularmeans or features embodied at or within the syringe arrangementsurrogate. Advantageously, the holder of the FTM validation apparatusis, or comprises, a construction separate or separable from the syringearrangement surrogate.

In particular, the holder may connect, on one side, to the force testingmachine and, on the other side, to a part of the syringe arrangement orits surrogate.

The FTM validation apparatus according to the invention allows forefficiently and accurately validating a test process in which a FTM isused for testing syringe arrangements or pharmaceutical products havingsyringe arrangements. Thereby, by providing the FTM validation apparatuswith the injection force part as well as the break loose force partallows for an improved mimicking of the forces involved in operation ofthe syringe arrangement. Like this, the operation of the syringearrangement can be better simulated such that the validation can be moreaccurate and reliable. Furthermore, the FTM validation apparatus allowsfor preventing waste of syringe arrangements or pharmaceutical productsduring validation and tuning of the test process.

Preferably, the syringe arrangement surrogate comprises a supportstructure which can be mounted to the holder. The mounting of thesupport structure can be such that a predefined distance is establishedbetween the surrogate or a specific portion thereof and the holder.

Preferably, the support structure is adjustable to accommodatedifferently dimensioned syringe arrangement surrogates which areconfigured to simulate corresponding differently dimensioned syringearrangements. Thus, the behavior of different sizes and types ofsyringes can be simulated. Also, the support structure may be configuredso that back pressure forces coming from the underlying injection forcepart are compensated. Furthermore, an anti-rotation feature may beincorporated in the support structure, such that under load the carrieris prevented from slipping from the grip of the support structure. Suchan anti-rotation feature may be conferred by a slider mechanism orsimilar, blocking the relative rotation of support structure andcarrier.

Preferably, the break loose part of the syringe arrangement surrogatehas a carrier and a distal plunger movable relative to the carrier in anaxial direction. In this case, the distal plunger may be connected tothe carrier such that it is releasable by applying a force correspondingto the break loose force of the syringe arrangement. The axial directionmay be the general direction of movement of the distal plunger and maycorrespond to the general longitudinal direction along which the overallforce testing machine validation apparatus extends. The syringearrangement surrogate and the holder may extend along a substantiallysame longitudinal or axial direction.

In connection with the invention, the term “distal” relates to adirection directed away from a body or person to which the syringearrangement, which is represented by the syringe arrangement surrogate,would be applied. Analogously, the term “proximal” relates to adirection towards the body or person to which the syringe arrangement,which is represented by the syringe arrangement surrogate, would beapplied. For example, in embodiments of syringe arrangements having aneedle intended to be pierced in the body or person and a plunger to bepushed for delivering a substance through the needle, the proximal endis formed by a tip of the needle and the distal end is formed by thesection of the plunger to be pushed.

Preferably, when the break loose part of the syringe arrangementsurrogate has a carrier as above described, the support structure of thesyringe arrangement surrogate fixedly holds the carrier and is mountablein relation to the injection force part. The mounting of the supportstructure is preferably such that a predefined correlation isestablished between the break loose part and the injection force part,suitable to simulate a given syringe arrangement with certainstandardized characteristics and dimensions.

Preferably, the carrier of the break loose part of the syringearrangement surrogate is equipped with a first magnetic element and thedistal plunger of the same break loose part of the syringe arrangementsurrogate has a second magnetic element. Thus, the distal plunger isconnected to the carrier by a magnetic force acting between the firstmagnetic element and the second magnetic element.

In particular, one of the first and second magnetic elements can be orcomprise a magnet and the other one of the first and second magneticelement can be made of a magnetic material such as an appropriate metalor the like, such that the abovementioned magnetic force can be exertedtherebetween. In such embodiments having first and second magneticelements, the magnetic force can be substantially equivalent, orproportional, to the break loose force of the syringe arrangement whichis being simulated via the syringe arrangement surrogate. When the FTMapplies a force on the distal plunger, such magnetic force has to beovercome in order to allow a further operation of the syringearrangement surrogate. This allows for suitably mimicking the breakloose force of the corresponding syringe arrangement. By way of example,the distal plunger can incorporate a metal disc and the carrier can beprovided with an array of cylindrical magnets or similar, possiblyaccommodated into the body of the carrier in dedicated recesses. Thedesign of the break loose part is such that, for the distal plunger tobe detached from the carrier, the FTM validation apparatus needs toapply a break loose force greater than the magnetic force existingbetween the metal disc and the carrier.

Preferably, the break loose part of the syringe arrangement surrogatecomprises an adjustable spacer structure arranged between the firstmagnetic element of the carrier and the second magnetic element of thedistal plunger. By the provision of such a spacer structure, a distancebetween the first magnetic element of the carrier and the secondmagnetic element of the distal plunger is adjustably predefinable. Sucha spacer structure allows for efficiently tailoring the FTM validationapparatus to the situation given in the syringe arrangement to bemimicked. Thereby, the spacer structure can comprise a set of plates orsheets, for instance Mylar discs, arrangeable between the first andsecond magnetic elements. By placing an appropriate amount of plates orsheets between the magnetic elements, an adjustment of the distancebetween the first and second magnetic elements is enabled and, as aconsequence, the magnetic force therebetween can be accurately defined.Additionally, or alternatively, the plates or sheets may be embodiedwith differing width such that a plate or sheet having an appropriatewidth can be chosen for adjusting the magnetic force.

Furthermore, the break loose part of the syringe arrangement surrogatemay comprise a distal sleeve displaceably arranged in the carrier,wherein the distal plunger axially extends through distal sleeve whenbeing connected to the carrier. Such a distal sleeve can allow forbetter holding and guiding of the distal plunger. Advantageously, thedistal sleeve comprises a bore or a through hole extending in the axialdirection, through which the distal plunger is arranged.

The injection force part of the syringe arrangement surrogate preferablycomprises a spring, an outer sleeve housing the spring and anintermediate plunger assembly extending into the outer sleeve. Inparticular, a first rod member of the intermediate plunger assembly maybe movable relative to the outer sleeve in an axial direction and thespring may be arranged to be deformed when the first rod member is movedin the axial direction into the outer sleeve.

In the context of the present application, the term “spring” can relateto any element suitable for providing a resilient force when beingelastically deformed such as bent, compressed or the like. Typically,springs are elastic elements such that, once deformed, they tend to getback to their original form or shape. Thereby, they provide a force onany means hindering them to do so. In a simple and efficient embodiment,the spring can be a helical spring.

Moreover, the injection force part may comprise a further spring, aninner sleeve housing the further spring and a second rod memberextending into the inner sleeve. In this case, the second rod member canbe made movable relative to the inner sleeve in the axial direction andthe further spring can be arranged to be deformed when the second rodmember is moved in the axial direction into the inner sleeve.

Analogously to the case of the first rod movement, the term “deformed”in this connection can particularly relate to the spring beingcompressed, bent or the like.

Such an arrangement allows for accurately simulating the situation givenin many syringe arrangements. For example, one of the springs can beembodied to represent a friction between a plunger or a stopper thereofand a syringe body or barrel. Additionally, the same springs togetherwith the associated structures allow for mimicking an air bubble in thesyringe arrangement which has to be compressed before delivery of thesubstance starts. The other one of the springs can represent thebehavior of the substance to be delivered, which may depend onproperties of the substance such as its viscosity or the like.

In a specific embodiment, the spring-contrasted action of the first rodmember of the intermediate plunger assembly when moving relative to theouter sleeve can advantageously mimic the viscosity-related fluiddynamic resistance, or drag, exerted by the pharmaceutical substancelocated inside the syringe body or barrel. Conversely, thespring-contrasted action of the second rod member when moving relativeto the inner sleeve can advantageously mimic the above friction betweena plunger, or a stopper thereof, and the syringe body or barrel, and/orthe compression of an air bubble within the syringe arrangement.

It is possible that, for specific embodiments of the invention, thesecond rod member moves relative to the inner sleeve before the firstrod member starts moving relative to the outer sleeve. The movement ofthe first rod member can actually be induced by an advancement of thesecond rod member and triggered by the establishing of a consequentcontact between the second and the first rod member. Preferably, theinner sleeve is made slidable within the outer sleeve.

In particular embodiments, the first and second rod members of theintermediate plunger assembly are designed to come to engage each other,after the second rod member has slid axially towards the first rodmember. After engaging, the first and the second rod members can move asone integral piece, as the first rod member further slides along theouter sleeve until it contacts a component of a needle safety deviceactivation force part.

Preferably, the intermediate plunger assembly is equipped with a roundedor essentially spherical distal end portion. Particularly, theintermediate plunger assembly preferably comprises a ball lying on thesecond rod member thereby forming the rounded distal end portion. Theball can, e.g. have a diameter of 12 millimeter and be loosely ormovably held in a respective concave recess of the second rod member.Such rounded distal end portion allows for simulating a human interface,such as a finger or the like. Thus, the rounded distal end portionallows for balancing deviations or inclinations of the syringe plunger,following the manipulation by an individual making use of the simulatedsyringe arrangement.

For this purpose, the distal end portion of the intermediate plungerassembly of the injection force part preferably contacts a proximal endof the distal plunger of the break loose part, when the holder supportsthe syringe arrangement surrogate in the predefined position andorientation in the force testing machine.

A third, additional part of the syringe arrangement surrogate of the FTMvalidation apparatus according to the present invention may preferablycomprise a needle safety device activation force part, arranged to mimica needle safety device activation force of the syringe arrangement.

In connection with the invention, the term “needle safety device”,abbreviated by the acronym NSD, relates to an arrangement which protectsa user or operator of the syringe from the needle. A NSD typicallycomprises a sleeve covering the needle, after the syringe has been used.For example, pushing a plunger rod of the syringe for administering aprefilled medicament, or drug substance, may trigger a mechanism of theNSD to move the sleeve such that it covers the needle. Typically, a NSDcomprises an initially tensioned spring and a release structureinteracting with the moving plunger rod. Once the plunger rod is movedfor pushing the drug substance out of the syringe via the needle to asufficient extent, the release structure activates the spring whichpushes the sleeve to be moved aside or around the needle.

The needle safety device activation force, can be the force needed totrigger a mechanism of the NSD of a syringe arrangement, such that arelease structure is activated by the syringe plunger movement to makethe needle inaccessible once the pharmaceutical substance has beeninjected.

The needle safety device activation force part of the syringearrangement surrogate preferably comprises a connector arranged tocontact the intermediate plunger assembly of the injection force partwhen being advanced by the force testing machine. To this purpose, theconnector can be plunger or rod shaped and it can extend into the axialdirection.

Preferably, the needle safety device activation force part of thesyringe arrangement surrogate comprises a body which releasably holdsthe connector with a force corresponding to the needle safety deviceactivation force of the syringe arrangement.

By further equipping the FTM validation apparatus with the needle safetydevice activation force part, syringe arrangement having such NSD can besimulated more accurately. This may improve the overall quality of thevalidation for many types of syringe arrangements.

In order to achieve the releasable holding between connector and body,the connector is preferably equipped with a third magnetic element andthe body is equipped with a fourth magnetic element, wherein theconnector is held by the body by means of a magnetic force actingbetween the third magnetic element and the fourth magnetic element.

Preferably, the needle safety device activation force part of thesyringe arrangement surrogate comprises a final spring arranged to bedeformed when the connector is moved in the axial direction. The body ofthe needle safety activation part may comprise a hollow interior housingthe final spring and integrating an opening through which the connectoris providable towards the final spring.

Another aspect of the invention relates to a method of validating a testprocess involving a force testing machine to measure forces involved inoperation of a syringe arrangement. The method comprises the steps of:obtaining a FTM validation apparatus as above described; customizing theFTM validation apparatus to the properties of the syringe arrangement;adjusting the force testing machine according to the syringearrangement; providing the FTM validation apparatus into the forcetesting machine, and operating the force testing machine for apredefined number of cycles. Such a method allows for efficientlyachieving the effects and benefits described above in connection withthe FTM validation apparatus and its preferred embodiments.

Preferably, customizing the FTM validation apparatus comprisespreliminary steps of evaluating a break loose force of the syringearrangement; an injection force of the syringe arrangement and a needlesafety device activation force of the syringe arrangement. Once theseforces have been evaluated, the customization of the adjustment of theforce testing machine can be finalized in accordance with the evaluatedbreak loose force, the evaluated injection force and the evaluatedneedle safety device activation force.

Customizing the FTM validation apparatus to the properties of thesyringe arrangement may comprise the step of simulating a break looseforce and/or an injection force and/or a needle safety device activationforce of the syringe arrangement by generating a respective magneticforce and/or spring force.

Preferably, generating a magnetic force as above introduced comprisesadjusting the force strength by an interposition of an adjustable spacerstructure between a first magnetic element and a second magnetic elementconfigured to create the magnetic force. The spring force(s) can beadjusted by choosing and/or appropriately pre-tensioning the respectivespring(s).

A further other aspect of the invention relates to a method of measuringforces involved in an operation of a syringe arrangement. Such methodcomprises the steps of defining a test process using a force testingmachine; validating the test process according to a validation method asabove described; and testing the syringe arrangement in the validatedtest process.

A still further other aspect of the invention relates to a use of a FTMvalidation apparatus as described above for validating a test processusing a force testing machine to measure forces involved in operation ofa syringe arrangement. Such a use allows for efficiently achieving theeffects and benefits described above in connection with the FTMvalidation apparatus and its preferred embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

The force testing machine validation apparatus according to theinvention, and the method of validating a test process involving a forcetesting machine by such a FTM validation apparatus according to theinvention are described in more detail herein below by way of anexemplary embodiment and with reference to the attached drawings, inwhich:

FIG. 1 shows a perspective view of an embodiment of a force testingmachine (FTM) validation apparatus according to the present invention;

FIG. 2A shows a perspective view of a syringe arrangement surrogate ofthe FTM validation apparatus of FIG. 1 equipped with a support structurefor holding a break loose force part of the syringe arrangementsurrogate in a predefined position relative to other parts of the FTMvalidation apparatus;

FIG. 2B shows a perspective view of the syringe arrangement surrogate ofthe FTM validation apparatus of FIG. 1 without the support structureshown in FIG. 2A;

FIG. 2C shows a cross section of the syringe arrangement surrogate ofthe FTM validation apparatus of FIG. 1 ;

FIG. 3 shows an exploded view of a break loose part of the syringearrangement surrogate of FIG. 2B;

FIG. 4 shows a cross section of an injection force part of the syringearrangement surrogate of FIG. 2C;

FIG. 5 shows a cross section of a needle safety device activation forcepart of the syringe arrangement surrogate of FIG. 2C;

FIG. 6 shows a holder arranged to support the syringe arrangementsurrogate of FIG. 1 when validating a test process involving a FTM andto support the syringe arrangement when testing the syringe arrangementin the FTM; and

FIG. 7 shows a sequence of perspective cross-section views of a syringearrangement, which can be equivalently simulated by the syringearrangement surrogate of FIGS. 2A, 2B and 2C, showing respectiveconfigurations taken by the syringe arrangement from an initial statewhere a syringe plunger is extended and a syringe needle is protected bya rigid needle shield, to a final configuration where the plunger hasbeen pushed to empty the syringe barrel via the needle and a mechanismof a needle safety device has been triggered to cover the needle.

DESCRIPTION OF EMBODIMENTS

In the following description certain terms are used for reasons ofconvenience and are not intended to limit the invention. The terms“right”, “left”, “up”, “down”, “under” and “above” refer to directionsin the figures. The terminology comprises the explicitly mentioned termsas well as their derivations and terms with a similar meaning. Also,spatially relative terms, such as “beneath”, “below”, “lower”, “above”,“upper”, “proximal”, “distal”, and the like, may be used to describe oneelement's or feature's relationship to another element or feature asillustrated in the figures. These spatially relative terms are intendedto encompass different positions and orientations of the devices in useor operation in addition to the position and orientation shown in thefigures. For example, if a device in the figures is turned over,elements described as “below” or “beneath” other elements or featureswould then be “above” or “over” the other elements or features. Thus,the exemplary term “below” can encompass both positions and orientationsof above and below. The devices may be otherwise oriented (rotated 90degrees or at other orientations), and the spatially relativedescriptors used herein interpreted accordingly. Likewise, descriptionsof movement along and around various axes include various special devicepositions and orientations.

To avoid repetition in the figures and the descriptions of the variousaspects and illustrative embodiments, it should be understood that manyfeatures are common to many aspects and embodiments. Omission of anaspect from a description or figure does not imply that the aspect ismissing from embodiments that incorporate that aspect. Instead, theaspect may have been omitted for clarity and to avoid prolixdescription. In this context, the following applies to the rest of thisdescription: If, in order to clarify the drawings, a figure containsreference signs which are not explained in the directly associated partof the description, then it is referred to previous or followingdescription sections. Further, for reason of lucidity, if in a drawingnot all features of a part are provided with reference signs it isreferred to other drawings showing the same part. Like numbers in two ormore figures represent the same or similar elements.

With initial reference to FIG. 1 , a force testing machine (FTM)validation apparatus 1 according to the present invention is shown,especially conceived for validating a test process involving a forcetesting machine to measure forces involved in operation of a syringearrangement 7 such as the one represented in FIG. 7 .

Relatively to the specific embodiment represented, the FTM validationapparatus 1 of FIG. 1 is particularly adapted to measure forces inconnection with the syringe arrangement 7 which comprises a staked-inneedle prefilled syringe 8 and a needle safety device 9, 9′, 9″cooperating with the staked-in needle prefilled syringe 8 as representedin FIG. 7 .

The FTM validation apparatus 1 comprises a syringe arrangement surrogate2, as it will be more in detail explained in connection with FIGS.2A-2C; and a holder 3 arranged to support the syringe arrangementsurrogate 2 in a predefined position and orientation in the FTM.

The syringe arrangement surrogate 2 and the holder 3 extend along asubstantially corresponding longitudinal, or axial, direction A. Also,the FTM validation apparatus 1 is designed so that the axial direction Asubstantially corresponds to the general direction of movement of itscomponents which are configured to simulate the operation of the syringearrangement 7.

As shown in FIG. 6 , the holder 3 may comprise a connector 31 foraccurate positioning in the FTM. The holder 3 may further comprise abase plate 32 and a top plate 33, which are held in place by amultiplicity of posts 34 extending along the axial direction A. Theconnector 31 can advantageously be integral with the base plate 32. Thebase plate 32 also integrates a socket 35 which is configured to receiveand stabilize a proximal portion of the syringe arrangement surrogate 2.The top plate 33 incorporates a connection to the syringe arrangementsurrogate 2. Different top plates 33 and/or base plates 32 can bemounted at respective extremities of appropriately elongated posts 34,in order to accommodate and test syringe arrangement surrogatesmimicking respectively differently sized syringe arrangements. By way ofexample, different sets of base and/or top plates and/or posts can beemployed to simulate syringe arrangements containing respectively 1.0millilitre or 2.25 millilitres. Advantageously, the same holder 3 usedwith the FTM validation apparatus 1 is also used in the testing process.Therefore, it is embodied to carry the syringe arrangement 7 to betested in the validated testing process. For example, the top plate 33can be equipped with a recess corresponding to the finger flange of thesyringe arrangement 7 to be tested. Such holder 3 allows for includingits appropriate functioning in the validation process.

With reference to FIGS. 2A-2C, the syringe arrangement surrogate 2comprises a break loose part 4, arranged to mimic a break loose force ofthe syringe arrangement 7, and an injection force part 5, arranged tomimic an injection force of the syringe arrangement 7.

With particular reference to FIG. 3 , the break loose part 4 has acarrier 41 and a distal plunger 42 movable relative to the carrier 41 inthe axial direction A. The plunger 42 is connected to the carrier 41such that it is releasable by applying a force corresponding to thebreak loose force of the syringe arrangement 7.

FIGS. 2C and 3 show how the carrier 41 is equipped with a first magneticelement 43, whereas the distal plunger 42 has a second magnetic element44. Thus, the distal plunger 42 is connected to the carrier 41 by amagnetic force acting between the first magnetic element 43 and thesecond magnetic element 44.

Relative to the specific embodiment represented, the distal plunger 42incorporates, or is attached to, a metal disc 44, and the carrier 41 isprovided with an array of cylindrical magnets 43 or similar,accommodated into the body of the carrier 41 in dedicated recesses, orslots. The recesses designed to receive the cylindrical magnets 43 aredistributed according to a substantially circumferential pattern aroundthe bore letting the plunger 42 slide through. The magnitude of themagnetic force acting between the metal disc 44 and the cylindricalmagnets 43 can be thus also customized based on the number ofcylindrical magnets introduced in the carrier 41, according to a modularconcept.

Moreover, the break loose part 4 of the syringe arrangement surrogate 2comprises an adjustable spacer structure 45 arranged between the firstmagnetic element 43 of the carrier 41 and the second magnetic element 44of the distal plunger 42. A distance between the first magnetic element43 of the carrier 41 and the second magnetic element 44 of the distalplunger 42 is therefore made adjustably predefinable. Consequently, afurther flexibility is offered in the calibration of the magnetic forceacting between the metal disc 44 and the cylindrical magnets 43. Asexplained, such a spacer structure 45 allows for efficiently adapting oradjusting the break loose force of the FTM validation apparatus 1 to thesituation given in the syringe arrangement 7 to be mimicked. Thereby,the spacer structure 45 can comprise a set of plates or sheets, forinstance Mylar discs, arrangeable between the first and second magneticelements 43, 44.

In FIGS. 1 and 2A it is shown that the break loose part 4 of the syringearrangement surrogate 2 comprises a support structure 46 fixedly holdingthe carrier 41. The support structure 46 is mounted such that the breakloose part 4 and the injection force part 5 are held in a predefinedrelationship to each other which reflects, or is characteristic of, thesimulated syringe arrangement 7.

In fact, the support structure 46 is adjustable to accommodatedifferently embodied syringe arrangement surrogates 2, configured tosimulate corresponding differently embodied syringe arrangements 7. Thesupport structure, in the form of two side supports 46 of the carrier41, is engineered to compensate the back pressure coming from theoperation of the injection force part 5. Moreover, the support structurecan comprise a slide mechanism which locks relative rotation andprevents the reciprocal slipping of carrier and supports 46, under load.

The break loose part 4 comprises also a distal sleeve 47 mounted to thecarrier 41 in an axially displaceable manner, wherein the distal plunger42 axially extends through the distal sleeve 47 when being connected tothe carrier 41. The sleeve 47 has a stabilizing effect on the plunger42.

With particular reference to FIGS. 2C and 4 , the injection force part 5of the syringe arrangement surrogate 2 has a spring 52, an outer sleeve51 housing the spring 52 and an intermediate plunger assembly extendinginto the outer sleeve 51. A first rod member 53 a of the intermediateplunger assembly is movable relative to the outer sleeve 51 in an axialdirection A and the spring 52 is arranged to be deformed when the firstrod member 53 a is moved in the axial direction A into the outer sleeve51. Advantageously, the outer sleeve 51, the rod member 53 a and thespring 52 cooperate to closely reproduce the fluid dynamic resistance,or drag, exerted by the pharmaceutical substance, located inside thesyringe body 14 of the syringe arrangement 7, on account of itsviscosity.

Moreover, the intermediate plunger assembly of the injection force part5 has a further spring 54, an inner sleeve 55 housing the further spring54 and a second rod member 53 b extending into the inner sleeve 55. Thesecond rod member 53 b is movable relative to the inner sleeve 55 in theaxial direction A and the further spring 54 is arranged to be deformedwhen the second rod member 53 b is moved in the axial direction A intothe inner sleeve 55. Advantageously, the inner sleeve 55, the second rodmember 53 b and the further spring 54 cooperate to simulate the frictionbetween the plunger stopper 13 and the internal walls of a syringe body14 of the syringe arrangement 7, which especially needs to be overcometo initiate the movement of the plunger 11. Additionally, this structureallows for mimicking the plunger movement prior the liquid to bedispensed is reached. In particular, the compression of an air bubble inthe syringe arrangement 7 before the liquid is dispensed can besimulated.

The intermediate plunger assembly is also equipped with a rounded distalend portion 56. In this case, the distal end portion 56 is formed by aspherical ball with a diameter of 12 millimeter, which is loosely ormovably held in a respective concave recess of the second rod member 53b. Such rounded distal end portion 56 or ball allows for simulating ahuman interface such as a finger or the like and it therefore allows forbalancing deviations or inclinations of the syringe plunger 11. Thespherical distal end portion 56 of the intermediate plunger assembly ofthe injection force part 5 contacts a proximal end of the distal plunger42 of the break loose part 4, when the holder 3 supports the syringearrangement surrogate 2 in the predefined position and orientation inthe force testing machine. In particular, in the shown configuration,the spherical distal end portion 56 contacts the second magnetic element44.

Under the load applied by the plunger 42 via the magnetic element 44detaching from the carrier 41, the second rod member 53 b moves relativeto the inner sleeve 55, before the first rod member 53 a starts movingrelative to the outer sleeve 51. The movement of the first rod member 53a is actually induced by the advancement of the second rod member 53 band triggered by establishing sufficient pressure from the second rodmember 53 b to the first rod member 53 a via the compressed furtherspring 54 or by the second rod member 53 b abutting the inner sleeve 55,which is in contact with first rod member 53 a, whatever happensearlier. After the sufficient pressure or abutting therebetween isestablished, the first rod member 53 a and the second rod member 53 bmove together substantially integrally. By advancing in the axialdirection A, the second rod member 53 b can also drag the inner sleeve55, which comes to move within the outer sleeve 51, up to the point whenthe first rod member 53 a abuts a connector 61 of the needle safetydevice activation force part 6. In this configuration, the inner sleeve55 is made slidable within the outer sleeve 51, which has a firstprotrusion 57 at its top end. Furthermore, the outer sleeve 51 isequipped with a second protrusion 58 designed to be equivalent to anextended finger flange 16 of the respective syringe arrangement 7.

Furthermore, the syringe arrangement surrogate 2 comprises a needlesafety device activation force part 6, arranged to mimic a needle safetydevice activation force of the syringe arrangement 7.

The needle safety device activation force part 6 comprises a stamp likeor T-shaped connector 61 arranged to contact the intermediate plungerassembly of the injection force part 5 when being advanced by the forcetesting machine. Relatively to the represented embodiment, as shown inFIG. 2C, the connector 61 comprises a rod-like part which is configuredto slide within the outer sleeve 51 of the injection force part 5. Theload from the force testing machine is transmitted to the connector 61when first rod member 53 a abuts the connector 61 which presses itoutwardly of the outer sleeve 51.

With reference to FIG. 5 , the needle safety device activation forcepart 6 of the syringe arrangement surrogate 2 comprises a body 69 whichis arranged to releasably hold the connector 61 with a forcecorresponding to the needle safety device activation force. The body 69has cylindrical portion 62 with a hollow interior which is closed at itsupper end by a top plate 67 fixed to the cylindrical portion 62 byscrews and at its lower end by a bottom plate 68 fixed to thecylindrical portion 62 by screws and pins. For providing the mentionedforce corresponding to the needle safety activation device, theconnector 61 is equipped with a horizontal plate-like third magneticelement 64. Thereby, the connector 61 is held relative to the body 69 bymeans of a magnetic force acting between the third magnetic element 64and the top plate 67 which, like this, forms a fourth magnetic elementstationary to the body 69. In FIG. 5 , the needle safety deviceactivation part 6 is shown in a state where the needle safety activationforce is overcome already, i.e. the third magnetic element 64 isreleased from the top plate 67 and moved downwardly. The situation wherethe third magnetic element 64 is still connected to the top plate 67and, thus, the needle safety activation force is not yet overcome, canbe seen in FIG. 2C.

The needle safety device activation force part 6 of the syringearrangement surrogate 2 comprises a final spring 65 arranged to bedeformed when the connector 61 is moved in the axial direction A. Thehollow interior of the body 69 houses the final spring 65 wherein it isclamped in between pre-tensioning disks 63 located on the bottom plate68 and a pre-tensioning disk 63 located below the third magnetic element64. The pre-tensioning disks 63 are made of a non- or low-magneticmaterial such as Aluminium or the like for preventing a magnetic forceacting between it and the third magnetic element 64. In the top plate 67an opening 66 is provided through which the rod-like part of theconnector 61 extends towards the final spring 65.

In FIG. 7 , the functioning of a needle safety device in connection withsubsequent phases of an operation of a syringe arrangement 7 comprisinga syringe 8 is shown. The needle safety device comprises a guard body 9;a spring 9″ deployed between the guard body 9 and the syringe barrel 14;and a release structure comprising a system of elastic fingers 9′. Whenthe plunger 11 is still extended in its initial distal position outsideof the syringe barrel 14 and the pharmaceutical substance has not yetbeen delivered, the guard body 9 fits over the syringe barrel 14 and thespring 9″ is in a compressed state. When it is intended to perform aninjection, the needle shield 15 is removed and the plunger 11 is pushedforward in a proximal direction towards the needle 10 by applyingpressure to a plunger flange 12. The plunger 11 is moved for pushing thepharmaceutical substance out of the syringe 8 via the needle 10, untilthe injection of the full dose has been completed. Consequently, therelease structure activates, triggered by deformation of the elasticfingers 9′, and the spring 9″ expands pushing the syringe 8 back so thatthe needle 10 comes to be fully protected and covered by the guard body9.

Customized based on the characteristics of the syringe arrangement to besimulated, the FTM validation apparatus according to the presentinvention allows to replicate the full range of forces involved in theoperation of such syringe arrangement, in each of the break loose forceregion, injection force region and needle safety device activation forceregion.

This description and the accompanying drawings that illustrate aspectsand embodiments of the present invention should not be taken as limitingthe claims defining the protected invention. In other words, while theinvention has been illustrated and described in detail in the drawingsand foregoing description, such illustration and description are to beconsidered illustrative or exemplary and not restrictive. Variousmechanical, compositional, structural, electrical, and operationalchanges may be made without departing from the spirit and scope of thisdescription and the claims. In some instances, well-known circuits,structures and techniques have not been shown in detail in order not toobscure the invention. Thus, it will be understood that changes andmodifications may be made by those of ordinary skill within the scopeand spirit of the following claims. In particular, the present inventioncovers further embodiments with any combination of features fromdifferent embodiments described above and below.

The disclosure also covers all further features shown in the Figs.individually although they may not have been described in the afore orfollowing description. Also, single alternatives of the embodimentsdescribed in the figures and the description and single alternatives offeatures thereof can be disclaimed from the subject matter of theinvention or from disclosed subject matter. The disclosure comprisessubject matter consisting of the features defined in the claims or theexemplary embodiments as well as subject matter comprising saidfeatures.

Furthermore, in the claims the word “comprising” does not exclude otherelements or steps, and the indefinite article “a” or “an” does notexclude a plurality. A single unit or step may fulfil the functions ofseveral features recited in the claims. The mere fact that certainmeasures are recited in mutually different dependent claims does notindicate that a combination of these measures cannot be used toadvantage. The terms “essentially”, “about”, “approximately” and thelike in connection with an attribute or a value particularly also defineexactly the attribute or exactly the value, respectively. The term“about” in the context of a given numerate value or range refers to avalue or range that is, e.g., within 20%, within 10%, within 5%, orwithin 2% of the given value or range. Components described as coupledor connected may be electrically or mechanically directly coupled, orthey may be indirectly coupled via one or more intermediate components.Any reference signs in the claims should not be construed as limitingthe scope.

What is claimed is:
 1. A force testing machine (FTM) validationapparatus for validating a test process using a force testing machine tomeasure forces involved in operation of a syringe arrangement,particularly a syringe arrangement comprising a staked-in needleprefilled syringe and a needle safety device cooperating with thestaked-in needle prefilled syringe, comprising: a syringe arrangementsurrogate; and a holder arranged to support the syringe arrangementsurrogate in a predefined position and orientation in the force testingmachine, wherein the syringe arrangement surrogate comprises a breakloose part arranged to mimic a break loose force of the syringearrangement and an injection force part arranged to mimic an injectionforce of the syringe arrangement, wherein the injection force part ofthe syringe arrangement surrogate has a spring, an outer sleeve housingthe spring and an intermediate plunger assembly extending into the outersleeve, wherein a first rod member of the intermediate plunger assemblyis movable relative to the outer sleeve in an axial direction and thespring is arranged to deform when the first rod member is moved in theaxial direction into the outer sleeve, and wherein the break loose partof the syringe arrangement surrogate has a carrier and a distal plungermovable relative to the carrier in an axial direction, and the distalplunger is connected to the carrier such that it is releasable byapplying a force corresponding to the break loose force of the syringearrangement.
 2. The FTM validation apparatus according to claim 1,wherein the carrier of the break loose part of the syringe arrangementsurrogate is equipped with a first magnetic element and the distalplunger of the break loose part of the syringe arrangement surrogate hasa second magnetic element, wherein the distal plunger is connected tothe carrier by a magnetic force acting between the first magneticelement and the second magnetic element.
 3. The FTM validation apparatusaccording to claim 2, wherein the break loose part of the syringearrangement surrogate comprises an adjustable spacer structure arrangedbetween the first magnetic element of the carrier and the secondmagnetic element of the distal plunger, such that a distance between thefirst magnetic element of the carrier and the second magnetic element ofthe distal plunger is adjustably predefinable.
 4. The FTM validationapparatus according to claim 1, wherein the syringe arrangementsurrogate comprises a support structure that is configured to bemountable to the holder.
 5. The FTM validation apparatus according toclaim 4, wherein the support structure is adjustable to accommodatesyringe arrangement surrogates of different dimensions that areconfigured to simulate corresponding syringe arrangements of differentdimensions.
 6. The FTM validation apparatus according to claim 1,wherein the break loose part of the syringe arrangement surrogatecomprises a distal sleeve, wherein the distal plunger axially extendsthrough the distal sleeve when being connected to the carrier.
 7. TheFTM validation apparatus according to claim 1, wherein the intermediateplunger assembly of the injection force part has a further spring, aninner sleeve housing the further spring and a second rod memberextending into the inner sleeve, wherein the second rod member ismovable relative to the inner sleeve in the axial direction and thefurther spring is arranged to deform when the second rod member is movedin the axial direction into the inner sleeve.
 8. The FTM validationapparatus according to claim 7, wherein the intermediate plungerassembly is equipped with a rounded distal end portion.
 9. The FTMvalidation apparatus according to claim 8, wherein the intermediateplunger assembly comprises a ball lying on the second rod member thatforms the rounded distal end portion.
 10. The FTM validation apparatusaccording to claim 8, wherein the rounded distal end portion of theintermediate plunger assembly of the injection force part contacts aproximal end of the distal plunger of the break loose part, when theholder supports the syringe arrangement surrogate in the predefinedposition and orientation in the force testing machine.
 11. A method ofvalidating a test process using a force testing machine to measureforces involved in operation of a syringe arrangement, comprising:obtaining a FTM validation apparatus according to claim 1, customizingthe FTM validation apparatus to properties of the syringe arrangement,adjusting the force testing machine according to the syringearrangement, providing the FTM validation apparatus into the forcetesting machine, and operating the force testing machine for apredefined number of cycles.
 12. A method of operating a force testingmachine validation apparatus according to claim 1 for validating a testprocess using a force testing machine to measure forces involved inoperation of a syringe arrangement.
 13. A force testing machine (FTM)validation apparatus for validating a test process using a force testingmachine to measure forces involved in operation of a syringearrangement, particularly a syringe arrangement comprising a staked-inneedle prefilled syringe and a needle safety device cooperating with thestaked-in needle prefilled syringe, comprising: a syringe arrangementsurrogate; and a holder arranged to support the syringe arrangementsurrogate in a predefined position and orientation in the force testingmachine, wherein the syringe arrangement surrogate comprises a breakloose part arranged to mimic a break loose force of the syringearrangement and an injection force part arranged to mimic an injectionforce of the syringe arrangement, wherein the injection force part ofthe syringe arrangement surrogate has a spring, an outer sleeve housingthe spring and an intermediate plunger assembly extending into the outersleeve, wherein a first rod member of the intermediate plunger assemblyis movable relative to the outer sleeve in an axial direction and thespring is arranged to deform when the first rod member is moved in theaxial direction into the outer sleeve, and wherein the syringearrangement surrogate comprises a needle safety device activation forcepart arranged to mimic a needle safety device activation force of thesyringe arrangement.
 14. The FTM validation apparatus according to claim13, wherein the needle safety device activation force part of thesyringe arrangement surrogate comprises a connector arranged to contactthe intermediate plunger assembly of the injection force part when beingadvanced by the force testing machine.
 15. The FTM validation apparatusaccording to claim 14, wherein the needle safety device activation forcepart of the syringe arrangement surrogate comprises a body whichreleasably holds the connector with a force corresponding to the needlesafety device activation force.
 16. The FTM validation apparatusaccording to claim 15, wherein the connector is equipped with a thirdmagnetic element and the body is stationary to a fourth magneticelement, wherein the connector is held by the body by means of amagnetic force acting between the third magnetic element and the fourthmagnetic element.
 17. The FTM validation apparatus according to claim14, wherein the needle safety device activation force part of thesyringe arrangement surrogate comprises a final spring arranged todeform when the connector is moved in the axial direction.
 18. The FTMvalidation apparatus according to claim 17, wherein a body of the needlesafety device activation part comprises a hollow interior housing thefinal spring and an opening through which the connector is movabletowards the final spring.